The long-term objective of the proposed research project entitled "Clinical evaluation of novel methods for extending microneedle pore lifetime" is to improve current methods of transdermal drug delivery by increasing the lifetime of pores created from inserting microneedles into the skin. Improvement of transdermal drug delivery techniques (via the use of microneedles) would have important clinical implications by providing a less invasive means to deliver drugs systemically, which would lead to greater patient safety and compliance. This could also have strong implications in developing better treatments for alcoholism and opiate addiction, as this proposal examines the delivery of naltrexone (an opiate antagonist used for the treatment of opioid and alcohol abuse) following microneedle insertion. Effective transdermal delivery would be an excellent alternative to the current oral and parenteral formulations of naltrexone. The specific aims of the proposal include 1) inhibition of the cyclooxygenase (COX) pathway as a means to inhibit pore closure, 2) pharmacokinetic analysis of naltrexone to characterize pore lifetime following COX inhibition, and 3) employing small-interfering RNA (siRNA) methods to inhibit pore closure. The research methods will involve the use of in vitro and in vivo models (cell culture, qRT-PCR, ELISAs), animal models (hairless guinea pigs and Yucatan miniature pigs), and human studies. Many of the methods described in the proposal involve novel applications of commercially available products, or development of innovative means to improve transdermal drug delivery with the use of microneedles. Studying these compounds and delivery methods makes it feasible to do translational bioengineering and biopharmaceutical training research in human proof-of-concept studies.